17-acetyl-17-hydroxy-perhydrocyclopentenophenanthrenes, anils, and oximes thereof, and method of preparing them



Patented Nov. 19, 1946 17-ACETYL-17-HYDROXY PERHYDROCY-CLOPENTENOPHENANTHRENES, ANILS, AND OXILIES THEREOF, AND METHODOFPREPARING THEM Homer E. Stavely, Highland Park,'N. J assignor to E. R.Squibb & Sons, New York,'N. Y., a corporation of New York No Drawing.Application March 22, 1940, Serial No. 325,473

6 Claims. (01. 260-397. 1)

This invention relates to, and has for its object the provision of,compounds of the group consisting of 17acetyl-17-hydroxy-perhydrocyclopentenophenanthrenesespecially 1'7hydroxy-20-keto derivatives of compounds of the pregnane series-anils,and oximes thereof; and a process of preparing them. These compounds,notably A -pregnendiol-3,17-one-20 and derivatives thereof, areimportant as precursors of progesterone and compounds similar to thesuprarenal cortex hormone-s, since perhydrocyclopentenophenanthreneshaving a hydroxy group in the 3 position are readily oxidized to 3- ketocompounds.

In the following description and claims, the nomenclature and numberingsystem employed is that established by the American Chemical Societymonograph Chemistry of Natural Products Related to Phenanthrene by L. F.Fieser, published in 1936 by Reinhold Publishing Corporation, New Yorkcity. by compounds of the pregnane series is meant compounds which havethe hydrocarbon nucleus of pregnane or pregnene and which may alsoembody oxyand/or oxo-substituents.

. The compounds of this invention may be prepared by reacting aI'Z-ethynyl-l'l-hydroxy-perhydrocyclopentenophenanthrene (8. g. A -17-.ethynyl-androstendiol-S,17, or 17-ethynyl-estradiol) with an anilformingaromatic amine (e; g., aniline or toluidin) in the presence of amercuric compound (e. g. mercuric chloride). An excess of anilin may beemployed as the reaction medium, in which case, after the reaction hasproceeded for a week at room temperature (or for a shorter period at ahigher temperature), the excess anilin is removed bysteam distillation,and the reaction mixtureconsisting of a ketone (e. g. A-pregnendiol-3,17-0ne-20) and the corresponding anil-is recovered. Thereaction may also be effected in a two-phase solvent system consistingof benzene and water. Separation of the ketone from the anil may beefiected by means of Girards ketone reagent T, or by acetylating themixture, and separation of the sparingly soluble anil acetate from themuch more soluble ketone acetate.

The 17 ethynyl-17-hydroxy-perhyclrocyclopentenophenanthrenes mayconveniently be obtained from perhydrocyclopentenophenanthrenes having anuclear keto group (e. g. dehydroisoandrosterone) by reaction withacetylene in the presence of a tertiary alcoholate, as described in myapplication Serial No. 228,957,

2 filed September 8, 1938 (now 864, dated April 29; 1941). a

The following examples are illustrative or the invention:

Example 1 A mixture of 1 g. A -l'l-ethynyl-androstendibh 3,17, 500 mg.mercuric oxide, 0.3 cc. ether-boronfluoride catalyst [J. Am. Chem. Soc.,55, 2858 (1933)] and 5.0 cc. dry anilin is allowed to stand at roomtemperature for about a week. The excess aniline is then removed bysteam distillation, and the residue is cooled and saturated with H25.After 12-16 hours, the mixture is thoroughly extracted with ether, andthe extract is washed with water, dried over sodium sulfate, andevaporated to dryness; on crystallization of the residue fromaqueousmethanol, 500 mg. of A -pregnendi01-3,1'7-0ne-20-anil is obtained. Theproduct melts at 148 C. Another crystalline modification melting at 185is obtained by crystallizing from benzene petroleum ether. The reaction.may also be carried out by substituting mercuric chloride for themercuric oxide and ether-boron-fluoride catalysts in the foregoingprocedure. 1 l

The aqueous methanol mother liquor of the anil crystallization,.afterstanding about 10 days, yields another crop of crystals, the productbein A -pregnendio1-3,l7-one-20, which sinters at 158 0., and melts at161-163" CL The melting point may be raised somewhat byjremovirigf'thelast traces ofwater'; a j I l ,Emample 2.1

3.0 g. A 17-ethynyl-androstendiol-3,17; '600 mg. mercuric chloride, and15 cc. water-free anilin are allowed to stand at room temperature for 8days. Excess anilin is removed by steam distillation, and the aqueousmixture saturated with HzS. After standing for 48 hours the mixture isextracted with ether, the. ether is evaporated, and the residue refluxedwith aqueous methanol for 28 hours. After cooling and the addition ofwater, a crystalline precipitate is obtained. The total product is driedand acetylated by reaction with acetic anhydride in pyridin for 12-16hours at room temperature. The solvent is removed by vacuumdistillation, and the residue dissolved in a large volume of methanol;on cooling, 700 mg. of crystalline A 3-acetoxy-pregnenol-17-one-20-anilis obtained. After recrystallization twice from methanolether, theproduct melts at 232-234 C. An additional 200 mg. yield may be obtainedfrom the mother liquor.

groups in said ring (the provision of which com- 7 pound is part of thesubject-matter of my application Serial No. 325,472, filedsimultaneously herewith, now Patent No. 2,357,364, dated Sep tember 5,1944). Thus, on refluxing 50 mg. of the ester with a 3% solution of KOHin methanol for two hours, neutralizing the alkali with CO2,

concentrating the solution, adding water, filtering the precipitate,washing with water, and crystallizing from acetone, hexagonal prismsmelting at 278-280 C. are obtained; the product is identical withaforementioned compound A.

Example 3 500 mg. A -17-ethynyl-androstendiol-3,17, 900 mg. mercuricchloride (2 moles), 150 mg. anilin (1 mole), cc. benzene, and 10 ccwater are refluxed together for hours. The benzene is removed by steamdistillatiom and the aqueous mixture is saturated with HzS and allowedto stand 48 hours-.. The mixture is then extracted with ether, theetherevaporated, and the dry residue acetylated by reacting with aceticanhydride in pyridin at room temperature for 12+16 hours. The solvent isremoved by vacuum distillation, and the acetates of A -pregnendio1-3,17-one-20 (140mg) and the corresponding anil (110 mg.) are separatedin themanner detailed inExample 2.

Example 4 and heated for about 2 hours. Water .is then .resulting.ketone acetate.

4. added, and the precipitate .formed is filtered, washed with water,dried, and recrystallized from benzene-petroleum ether. The product, A-3- acetoxy-pregnenol-17-one-20 oxime, melts at 254-256" C. l

" Example -6 A -3-acetoxy-pregnenol-1'7-one-20 is converted into thecorresponding oxime by reaction with hydroxylamine hydrochloride asdetailed in Example. 5. The product melts at 253-256 C., and

the mixed melting point with the product of Example 5 shows nodepression. This application is a continuation-in-part of my applicationSerial No. 246,861, filed December 20, 1938.

The invention may be variously otherwise em- "bodied within the scope ofthe appended claims.

I claim;

.1. The method which comprises reacting a 1'7 ethynyl1'1-hydroxy-perhydrocyclopentenophenanthrene with an anil-formingaromatic amine in the presence of a mercuric-compound catalyst. I

2. The method which comprises-reacting a 17 ethynyl 17hydroxy-perhydrocyclopentenophenanthrene with aniline in the presence ofa mercuric-compound catalyst.- l

3. The method of preparing a l l acetyl- 1'7hydro-xy-perhydrocyclopentenophenanthrene, which comprises reacting a17-ethynyl-17-hydroxy-perhydrocyclopentenophenanthrene w i t h anilinein the presence of a mercuric-compound catalyst, and recovering theketonefrom the reaction mixture.

4. The. method of preparing a -17-acety1- 17' hydro-xy-p erhydrocy c1opentenophen anthrene which comprises reacting a l'l-ethynyl-lfl-hydroxy-perhydrocyclopentenophenanthrenew it h aniline in thepresence of a mercuric-compound catalyst, treating the reaction mixtureto'con vertthe anil'to'the corresponding ketone, ac'etyl ating thereacti'on'mi'x'ture, and recovering the 5.'The method of preparingal7-hydroxy 20- keto derivative of a compound of theprgnane series, whichcomprises reactingthe corresponding 17-ethynyl-17-'hydroxy compound withan anil-forming aromatic amine'in the presenceof a mercuric-compoundcatalyst. -6.--The method of preparing A -pregnendiol-' 3,17'-one-20,'which comprises reacting A 4 7 ethynyl-androstendiol-3,17 with ananil-forming aromatic amine in the presence of a mercuric compoundcatalyst. f f HOMERI -E. STAVELY,-"

